Practical Considerations in Kinetic Resolution Reactions John M. Keith, Jay F. Larrow, Eric N. Jacobsen* Harvard University, Department of Chemistry and Chemical Biology, 12 Oxford Street, Cambridge, MA 02138, U.S.A. Fax: +1 617-4 96-18 80; e-mail: jacobsen@chemistry.harvard.edu Received October 19, 2000, Accepted October 25, 2000 1 Introduction The goal of asymmetric synthesis ± whether it is done in an academic or an industrial setting ± is to prepare stereochemically-enriched com- pounds in the most efficient and practical man- ner possible. However, the choice of strategy is rarely simple, because the ways in which effi- ciency and practicality are defined can depend on a large number of factors. These can include scale, reagent costs, time allotted and required, number of steps/manipulations, potential haz- ards, waste generation, specifications for pro- duct purity, volumetric productivity and/or throughput, availability of appropriate equip- ment, and even the scientific back- ground of the synthetic chemists in- volved. In selecting a method for the preparation of an enantioenriched com- pound, one must therefore consider the different alternatives. There are three fundamentally different approaches, [1] and these can be defined as follows: · Chiral pool: use of enantiopure start- ing materials provided by Nature. · Resolution: separation of enantiomers by chemical or physical means. · Enantioselective synthesis: preparation from achiral precursors using chiral reagents or catalysts. There are numerous instances where the chiral pool approach is unbeatable, either be- cause the requisite starting material is pro- duced by Nature in great abundance or because the target is itself a complex natural product and laboratory syntheses are very expensive relative to isolation from natural sources. Un- fortunately, the range of compounds provided by Nature is limited with respect to structure and stereochemistry, and for this reason reso- lution and asymmetric synthesis will certainly always be vitally important strategies for acces- sing enantiopure compounds. Resolution strategies have always played a central role in the preparation of optically ac- tive compounds. [2] However, and particularly recently, great effort has been directed toward avoiding such approaches due to what is per- ceived to be their inherent inelegance and inef- ficiency. This is due to the fact that, except in those rare cases where both enantiomers can be employed productively, resolutions have a maximum yield of 50% based on racemic start- ing material. In that respect, they can be seen as displaying inherently poor ªatom econo- myº. [3] Enormous advances have made over the past several years in asymmetric synthesis, [4] with particular emphasis having been placed on the development of enantioselective catalytic reac- tions. [5] The advantages associated with enan- tioselective synthesis are well-recognized, and can include: a) access to either enantiomer of product based on which enantiomer of re- agent/auxiliary/catalyst is employed; b) use of a readily-available achiral substrate; and c) minimization of waste typically associated with resolution processes. Different factors influence the practicality of an asymmetric reaction. A list of the features Adv. Synth. Catal. 2001, 343, No. 1 Ó WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2001 1615-4150/01/34301-5±26 $ 17.50-.50/0 5 REVIEWS Keywords: asymme- tric catalysis; cata- lysts; chiral resolu- tion; enantiomeric resolution; epoxida- tions; homogeneous catalysis Abstract: This review provides a critical analysis of catalytic ki- netic resolution reactions from a practical perspective, asking the question of when, if ever, is kinetic resolution the best option for the synthesis of an optically active target. A series of crucial condi- tions are identified, and it is postulated that if all of them are met, then indeed kinetic resolution can be highly practical. A variety of catalytic kinetic resolution processes are evaluated in the context of these criteria, with particular emphasis on catalyst availability, substrate scope, availability of the racemic substrate and of alter- native methods for accessing enantiopure substrate or product, and key experimental considerations. It is found that several cata- lytic systems have been developed that offer almost unbeatable methods for the preparation of useful chiral building blocks. Supporting information for this article is available on the WWW under http://www.wiley-vch.de/home/asc/ or from the author.